Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism.

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Authors

Kandaswamy, R
Sava, GP
Speedy, HE
Beà, S
Martín-Subero, JI
Studd, JB
Migliorini, G
Law, PJ
Puente, XS
Martín-García, D
Salaverria, I
Gutiérrez-Abril, J
López-Otín, C
Catovsky, D
Allan, JM
Campo, E
Houlston, RS

Document Type

Journal Article

Date

2016-08-23

Date Accepted

2016-07-20

Abstract

Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.

Citation

Cell reports, 2016, 16 (8), pp. 2061 - 2067

Source Title

Publisher

CELL PRESS

ISSN

2211-1247

eISSN

2211-1247

Research Team

Cancer Genomics
Molecular & Population Genetics

Notes